The genetic disorder Osteogenesis Imperfecta (OI) is characterized by low bone mass that predisposes children and adults to skeletal fracture. Most patients with OI have a mutation in one of the two genes that encode type 1 collagen. Current medical therapies for patients with OI are mostly anti-catabolic, acting by preventing bone turnover to increase bone mass. Unfortunately, these therapies are limited and inadequate. In proof of principle experiments, I have found that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling pathway leads to significant increases in bone mass and bone strength in two mouse models of OI. In the present application, I intend 1) to precisely define the mechanism(s) by which enhanced LRP5 signaling improves bone properties in these mouse models of OI, 2) to determine whether enhanced LRP5 signaling can improve bone properties in other mouse models of OI that are due to different type 1 collagen mutational mechanisms, and 3) to test whether prenatal administration of a neutralizing monoclonal antibody against sclerostin, an endogenous inhibitor of LRP5, is able to effect further improvements in bone properties and provide protection against immunogenicity-induced treatment resistance in comparison to postnatal anti-sclerostin antibody therapy. By addressing these aims, I will determine whether enhancing LRP5 signaling improves bone strength by increasing bone formation or by altering the repertoire of matrix proteins that are secreted by OI osteoblasts. I will also identify whether the type of mutation that causes OI determines whether enhancing LRP5 signaling will be beneficial or detrimental to human patients. Finally, using a mouse OI model, I will identify therapeutic strategies that best improve bone properties while minimizing the side effects of therapy.